Bicyclodecenes containing three ring nitrogen atoms



United States Patent 3,351 629 BICYCLODECENES CbNTAINING THREE RING NITROGEN ATOMS Rudolf G. Griot, Florham Park, N.J., assignor to 3,351,629 Patented Nov. 7, 1967 The primary m-amin-o acid, H N--RCOOH,- is one wherein R is more specifically defined as R -c-R Sandoz Inc., Hanover, NJ. 5 wherein each of R and R is, independently, either hy- No Drawing. Filed Apr. 1, 1964, Ser. No., 356,641 drogen (-H); lower alkyl, e.g. methyl, isopropyl and 7 Claims- 260-4095) butyl; hydroxy(lower) alkyl, e.g. a-hydroxyethyl; (lower) alkyl-thio-(lower)alkyl, e.g; methyl thioethyl; phenyl Thls mventlon concerns compounds of the formula (lower) alkyl, e.g. benzyl; substituted benzyl wherein the N 10 substituents comprise hydroxy (-OH), bromine (-Br) and/or iodine (I) and are directly bound to a ring I NH carbon atom, e.g. m,p-dihydroxybenzyl; indolyl(lower) alkyl, e.g. 3-indolylmethy1; imidazole(lower)alkyl, e.g. O (I) 4(or 5)-imidazolernethyl; or phenyl. wherein R is the residue of an a-(primary)amino mono- Alternatively, R1 and R2 together, either a saturated, carboxylic acid, H NRCOOH, which contains only pentarqethylene, an ethylenlcally Unsaturated, one primary amino group, e.g. pentad1enyl-1,3-, hydrocarbon chain of from 2 to therapeutically acceptable acid addition salts of said com- 3 carbon atomspounds (I), intermediates in the synthesis of said corn- Table A reflects some of the contemplated primary pounds (I) and processes for preparing any of the afore- 20 a-amino acids and the corresponding definitions of R said compounds. and R TABLE A Name Formula R R I 1 Glycine I GHANHQCOOH H H a-Alanine omontNrmooon 0H, 11 Serine HOCHZCH(NHQ)COOH H0011, H 4 Threonine CH3CH(OH)GH(NH2)COOH OH3CH(OH) H Valine (omnonomNnnoooH clamor: H l 6..- Methionine CH3S(CH2):CHQNH2)COOH OH3S(CH2)1 H Phenylalanine -QQ-ornonmnncoon om H 1131 Br Dibromotyrosine HO-CH1CH(NH)COOH G011, H

, it is l 1 9 Tryptophane --f HN HI? HC=CH1CH(NH;) 00 OH Ho=oorn H /CH /C& a" a i 10---- Histidine HC=CCH1OH(NHz)C0OH 110:0013, H 11.-.. a-Amino isobufyric acid v H2NO(CH3)qC OOH CH3 CH3 12. a-Phenylgl'ycine .lQ-onmnnooon n NH, 13.-.. a-Amino-eyclohexane carbonic acid. 0 H10 H20 H 0 HzCHg- 2 CODE 14.... a-Methyla-phenyl glycine H2N Ha)lC 00H Q CH:

according to the reactions:

R has the same meaning as hereinbefore defined. V V i i I Compounds (I) are also hydrogenated in an inert solvent according to well-known procedures with a platinum dioxide catalyst:

R H2 NH (I) Q O= N PtOa Compounds (VI) are further useful according to the reaction:

wherein R is either hydrocarbon (saturated-lower alkyl, e.g. methyl, ethyl and propyl; ethylenically unsaturated lower aliphatic, e.g. allyl; acetylenically unsaturated lower aliphatic, e.g. propargyl; monocarbocylic aryl, i.e. phenyl; monocarbocylic ar(lower)- alkyl, e.g. benzyl) or carboxylic acid acyl [unsubstituted phenyl-keto-(lower)alkyl, e.g. phenyl-ketopropyl; substituted phenyl-keto-(lower)-alky1, e.g. p-

fluorophenyl-keto-propyl; (lower)-alkyl-keto-(lower) alkyl, e.g. propyl-keto-ethyl]; Y is either chlorine (-Cl) or bromine (--Br); and R has the same meaning as hereinbefore defined.

Compounds (II), (VI), (VII), (X) and (XIII) and their pharmaoeutically acceptable acid addition salts are useful in the same manner and for the same therapeutic purpose as compounds (I). The acid addition salts are prepared according to Well-known procedures by neutralizing a solution of the free base with the acid of addition.

To afford an appreciation of the nature of the compounds and intermediates of the instant invention, a series of reaction schemes, illustrative of the utility of said compounds and intermediates, is presented. In the series, wherein each of R, R and Y has its previouslv ascribed meaning;

R has the same meaning as R;

Z has the same meaning as Y; and

AcOH means acetic acid,

starting from compound (III), which the title compound (h) of Example 4 is exemplary, compound (VI) is produced by conventional hydrogenation with a platinum catalyst. However, if only one molar equivalent of hydrogen is reacted, only the ring double bond is reduced to product compound (VIII). By a reaction comparable to (F) compound (VIII) is converted to compound (IX) which, upon further conventional hydrogenation, is transformed to compound (X). Reacting compound (X) with a halide, R Z, permits substitution on the remaining secondary nitrogen, i.e. the 4-position. Alternatively, treating compound (III) with a mixture of hydrobromic and acetic acids (see Example 5) results in splitting off the carbobenzoxy group without destroying the ring double bond, thus producing compound (I). The reaction of compound (I) with a halide, R Z, results in the substitution of R in the 4-position (compound XI). Conventional hydrogenation of compound (XI) reduces the ring double bond to produce compound (XII), which,

5 6 by a-reactioncomparable to (F), is converted into com- An elemental analysisreveals the folowing comparipound (XIII), son for .C H N O Calculated, percent: C, 62.9; H,

. v V E MEL; H

or HBr/AcOH o (VIII) 7 (IX) 7 (X) a 4 V O 7 1 WE 2R Y 2 (III) 1 ,5 (V

l usr Aooa' v 1 R z 2 9 5 [m2] (I), 0 (x1) (xii 1 The preparation .of compounds (I) is best illustrated 3 6.5; N, 11.3; 0, 19.3. Found, percent: C, 63.3; H, 6.6; by the following examples,- in which the parts and per- N, 11.1; 0, 19.1. centages are -by weight'unless otherwise specified and the temperatures are in degrees Centigrade. The relationship between parts by weight and parts by volume is. the

EXAMPLE 2' fam P btween thekilogram the liter- 40 1-carbobenzoxy-S-ethoxy-I,4-diazacycloheptane-A EXAMPLE 1 1-carbobenzoxy-I,4t1iazacycloheptane-S-one lg no i I (c) :Ha)a Ea-- J v 0 6N1; Ii kNH 1 f uro-c-ol-ee Over a period of 45 minutes and at a temperature of AdrmX: 21m of m P P hydrochlorlde from 20 to 25 add 5.70 parts of (c) [dissolved in Dlckefman, u and l, G': parts by volume of methylene chloride (CH Cl to i e 530 to 536 w In eXCeSS of one triethyloxoniumborofluoride' ((1), prepared from 4.65 equlvalefl} of concefluatedp q) Potash Solution- EXtl'act parts of epichlorohydrin and 10 parts of boron trifluoridethe resultmg base wlth chlor formetherate [see ,Meerwein;et al., I. Prakt. Chem., 154,

Dry the x r c potassium b nate 83 to 156 (1940 dissolved in 50 parts by volume of (K CQ and concentrate to 200 parts by volume. Add absolute CH CIQ. Stir the resulting reaction mixture at 53-5 partsof triethylarnineto said concentrate, and cool th b t d temperature f 15 h u a d then cool t resultant 3 Period of h y minutes add same to 5. Thereafter introduce therein 10 parts of 0-560 P CaKbObeBZOXYQhIOIidE (dissolved in 20 saturated (aq).- potassium carbonate (K CO Follow Parts y V l of 6111GT r dropwise to h Cooled said introduction by vigorous stirring of the produced readmixture. Stir the resultant at 0 for ninety minutes and actio mixture, thereafterat 120 for an additional ninety minutes. Separate the organic phase and dry same over K CO Add 10 parts of ice and 100 parts by volume of 2 N Remove the organic solvent in vacuo, leaving an oil, boilhydrochloric ac id to the resulting admixture, which subing point (B.P.) 110 t 115/0 0 5 Th are hus se uently separates into layers. Wash the organic phase obtained 5,5 parts of title'compound, having a refractive with 1) sodillmevbicl'rbonate Solution y the Washed index, .5 of 1.5290. Infrared spectra (5% in CH CI organic phase over magnesium sulfate Q- preveal adsorption at 1670 om. (strong c =N-). orate until a yellowoil remains. Add diethylether to the An elemental analysis permits the following compariyellow oil to effectcrystallizatron, melting point (M.P.)' son f r C I-I N O Cal u1ated, p'r'cent C, 65.2; H, 7.3;

110" to 112,"of the title compound (c). A yield of N, 10.1; 0, 17.4. Found, percent: C, 65.4;vH, 7.5; N, 10.2; 4.98 parts is thus obtained. O, 17.6.

7 EXAMPLE 3 1carbobenzoxy-l,4-a'iazacycl0heptyl-5-imino acetate acid I OH Stir overnight to 17 hours) at room temperature (about a mixture of 5.5 parts of (e) with a suspension of 1.5 parts of glycine (f) in 16 parts by volume of methanol. Filter and dry the crystalline precipitate (g), M.P. 183.5 to 184 which forms. A yield of 5.1 parts of the title compound, which is very hygroscopic, is thus obtained.

Infrared spectra (in KBr) reveal absorption (broad and strong) at 1710 CIIIC'I (indicative of carbobenzoxy and C=N) and strong at 1630 cm.- (indicative of COO An elemental analysis permits the following comparison for C H N O Calcu1ated, percent: C, 59.1; H, 6.6; N, 13.8; 0, 21.0. Found, percent: C, 59.0; H, 6.3; N, 13.6; 0, 21.0.

In place of glycine every other a-primary amino monocarboxylic acid having only one primary amino group reacts similarly to produce the corresponding product (XIV) according to the reaction:

In reaction (G) compound (XIV) is, for example, each of the a-amino acids enumerated in Table A.

EXAMPLE 4 4-carbobenzoxy-I,4,8-triazabicycl0 [5,3,0] decen-A' -1 O-one MLQ (H) (III) wherein R has the same meaning and scope as previously indicated.

The base (h) is a glasslike solid at 10. To prepare the corresponding hydrochloride, dissolve compound (h) in isopropanol, and neutralize the resulting isopropanolic solution with an isopropanolic solution of hydrogen chloride. Upon neutralization, the hydrochloride crystallizes. Recrystallize said hydrochloride, M.P. from isopropanol.

An elemental analysis of the hydrochloride,

m m a a provides the following comparison-Calculated, percent: C, 55.6; H, 5.6; N, 13.0; 0, 14.8; C1, 10.9. Found, percent; C, 55.6; H, N, 12.8; 0, 15.1; Cl, 10.9.

In similar manner acid addition salts are prepared from each compound (III). Exemplary of the acid addition salts are those which are pharmaceutically acceptable, such as fumarates, maleinates, tartrates, methane sulfonates, salicylates and hydrosulfates.

EXAMPLE 5 1,4,8-triaza-bicyclo [5,3,0] decen-A' -IO-One N HBr N (h) NH AcOH N Add 15 par-ts by volume of 4 N hydrogen bromide (in acetic acid) to 0.310 parts of compound (h). After 10 minutes at room temperature, the hydrobromide of compound (i) begins to precipitate. After 1 hour 'at room temperature, add 300 parts by volume of diethylether to the existing admixture to precipitate the rest of the salt. Thereafter, discard the solvent and crystallize the residue from methanol, M.P. 256 (dec.).

Infrared spectra (KBr) reveal absorption at 3420 cm? (indicative of NH--), strong absorption at 1800 cm." (indicative of N-(/ O) and medium absorption at 1655 cm.- (indicative of C=N-). An elemental analysis permits the following comparison for Calculated, percent: C, 26.7; H, 4.2; N, 13.3; Br, 50.7. Found, percent: C, 27.0; H, 4.7; N, 13.1; Br 50.6.

To free the base (i), admix aqueous potassium carbonate solution with the hydrobromide until the admixture is alkaline. Evaporate the obtained organic phase to produce the free base.

In similar manner all said addition salts of compounds referred to herein are converted to their corresponding free base. If the free base is a liquid, it is purified by distillation; if it is a solid, by recrystallization.

This example is illustrative of a class reaction:

EXAMPLE 6 1 carbobenzoxy-1,4,8-triazabicycl0 [5,3,0] decan-I O-one Dissolve 0.162 part of compound (h) in 25 parts by volume of methanol. To the resulting solution add 0.30 part of platinum oxide (PtO and pass hydrogen gas therethrough. After 1 mole of hydrogen is taken up (30 minutes), filter oil the catalyst, and evaporate the filtrate to dryness.

Infrared analyses 5% in CH CI reveal a broad band at 1700, indicating that the carbobenzoxy rest is still pres-- ent. No band is found for C=N.

This example is illustrative of a class reaction;

(III) wherein each of R and R is either, independently, a

member selected from the group consisting of a hydrogen atom, lower alkyl, hydroxy(lower)-alkyl, (lower) alkylthio(lower)alkyl, phenyl(lower)alkyl, indolyl (lower) alkyl, imidazole(lower) alkyl, phenyl, and benzyl ring-substituted with at least one substituent selected from the group consisting of hydroxy, bromo and iodo; or, both taken together with the carbon atom to which they are bound, form a carbocyclic ring having from 3 to 9 carbon atoms and being selected from the group consisting of a saturated hydrocarbon ring and an ethylenically unsaturated hydrocarbon ring.

2. The compound of the formula 3. A compound which, in its free base form, has the formula R2 Rat Y) NH U wherein each of R and R is, independently, a member selected from the group consisting of a hydrogen atom; lower alkyl; hydroxy(lower)alkyl; (lower)alkyl-thio- (lower)-alkyl; phenyl(lower)a'1kyl; benzyl ring-substituted with at least one substituent selected from the group consisting of hydroxy, a bromine atom and an iodine atom; indolyl(lower)alkyl; imidazoleflower) alkyl; and phenyl.

10 4. A compound which, in its free base form, has the formula R (N I I NH wherein R and R form, with the carbon atom to which they are both bound, at carbocyc-lic ring having from 3 to 9 carbon atoms and selected from the group consisting of a saturated hydrocarbon ring and an ethylenically unsaturated hydrocarbon ring. 5. The compound of the formula 6. A member selected from the group consisting of a compound and pharmaceutically acceptable salts thereof, the compound having the formula wherein each of R and R is either, independently, a

member selected from the group consisting of a hydrogen atom, lower alkyl, hydroxy(lower)alkyl, (lower)alkylthio(lower)alkyl, phenyl(lower)alkyl, indoly l(lower)alkyl, imidazole(lower)alkyl, phenyl, and benzyl ring-substituted with at least one substituent selected from the group consisting of hydroxy, bromo and iodo; or, both taken together with the carbon atom to which they are bound, form a carbocyclic ring having from 3 to 9 carbon atoms and being selected from the group consisting of a saturated hydrocarbon ring and an ethylenically unsaturated hydrocarbon ring; and

R is a member selected from the group consisting of a lower aliphatic hydrocarbon radical, phenyl, phenyl (lower)alkyl, phenyl-keto-(lower)alkyl and (lower) alkyl-keto-(lower)alkyl. 7. The compound of the formula References Cited UNITED STATES PATENTS 3,002,000 9/1961 Tietze et al. 260-3096 FOREIGN PATENTS 826,837 1/1960 Great Britain. 

1. A COMPOUND OF THE FORMULA 2-R2,2-R1,3-(O=),7-(PHENYL-CH2-OOC-)-2,3,5,6,8,9-HEXAHYDROWHEREIN EACH OF R1 AND R2 IS EITHER, INDEPENDENTLY, A MEMBER SELECTED FROM THE GROUP CONSISTING OF A HYDROGEN ATOM, LOWER ALKYL, HYDROXY(LOWER)ALKYL, (LOWER) ALKYLTHIO(LOWER)ALKYL, PHENYL(LOWER)ALKYL, INDOLYL (LOWER)ALKYL, IMIDAZOLE(LOWER)ALKYL, PHENYL AND BENZYL RING-SUBSTITUTED WITH AT LEAST ONE SUBSTITUTENT SELECTED FROM THE GROUP CONSISTING OF HYDROXY, BROMO AND IODO; OR, BOTH TAKEN TOGETHER WITH THE CARBON ATOM TO WHICH THEY ARE BOUND, FORM A CARBOCYCLIC RING HAVING FROM 3 TO 9 CARBON ATOMS AND BEING SELECTED FROM THE GROUP CONSISTING OF A SATURATED HYDROCARBON RING AND AN ETHYLENICALLY UNSATURATED HYDROCARBON RING.
 3. A COMPOUND WHICH, IN ITS FREE BASE FORM, HAS THE FORMULA 2-R2,2-R1,3-(O=)-2,3,5,6,8,9-HEXAHYDRO-7H-IMIDAZO(1,2-D)WHEREIN EACH OF R1 AND R2 IS, INDEPENDENTLY, A MEMBER SELECTED FROM THE GROUP CONSISTING OF A HYDROGEN ATOM; LOWER ALKYL; HYDROXY(LOWER)ALKYL; (LOWER)ALKYL-THIO(LOWER)ALKYL; PHENYL(LOWER)ALKYL; BENZYL RING-SUBSTITUTED WITH AT LEAST ONE SUBSTITUENT SELECTED FROM THE GROUP CONSISTING OF HYDROXY, A BROMINE ATOM AND AN IODINE ATOM; INDOLYL(LOWER)ALKYL; IMIDAZOLE(LOWER) ALKYL; AND PHENYL.
 4. A COMPOUND WHICH, IN ITS FREE BASE FORM, HAS THE FORMULA 2-R2,2-R1,3-(O=)-2,3,5,6,8,9-HEXAHYDRO-7H-IMIDAZO(1,2-D)WHEREIN R1 AND R2 FORM, WITH THE CARBON ATOM TO WHICH THEY ARE BOTH BOUND, A CARBOCYCLIC RING HAVING FROM 3 TO 9 CARBON ATOMS AND SELECTED FROM THE GROUP CONSISTING OF A SATURATED HYDROCARBON RING AND AN ETHYLENICALLY UNSATURATED HYDROCARBON RING.
 6. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, THE COMPOUND HAVING THE FORMULA 2-R2,2-R1,3-(O=),7-R5-2,3,5,6,8,9-HEXAHYDRO-7H-IMIDAZO7H-IMIDAZO(1,2-D)-1,4 -DIAZEPINE 1,4-DIAZEPINE 1,4-DIAZEPINE (1,2-D)-1,4-DIAZEPINE WHEREIN EACH OF R1 AND R2 IS EITHER, INDEPENDENTLY, A MEMBER SELECTED FROM THE GROUP CONSISTING OF A HYDROGEN ATOM, LOWER ALKYL, HYDROXY(LOWER)ALKYL, (LOWER)ALKYLTHIO(LOWER)ALYL, PHENYL(LOWER)ALKYL, INDOLY(LOWER)ALKYL, IMIDAZOLE(LOWER)ALKYL, PHENYL, AND BENZYL RING-SUBSTITUTED WITH AT LEAST ONE SUBSTITUENT SELECTED FROM THE GROUP CONSISTING OF HYDROXY, BROMO AND IODO; OR, BOTH TAKEN TOGETHER WITH THE CARBON ATOM TO WHICH THEY ARE BOUND, FORM A CARBOCYCLIC RING HAVING FROM 3 TO 9 CARBON ATOMS AND BEING SELECTED FROM THE GROUP CONSISTING OF A SATURATED HYDROCARBON RING AND AN ETHYLENICALLY UNSATURATED HYDROCARBON RING; AND R5 IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF A LOWER ALIPHATIC HYDROCARBON RADICAL, PHENYL, PHENYL (LOWER)ALKYL, PHENYL-KETO-(LOWER)ALKYL AND (LOWER) ALKYL-KETO-(LOWER)ALKYL. 